4-amino-imidazoquinoline compounds

ABSTRACT

This invention relates to novel 4-amino-imidazoquinoline compounds of the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 4  are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer or infectious diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of EuropeanPatent Application No. 14165349.3, filed Apr. 22, 2014, the contents ofwhich are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel 4-amino-imidazoquinolinederivatives having pharmaceutical activity, their manufacture,pharmaceutical compositions containing them and their potential use asmedicaments.

In particular, the present invention relates to compounds of the formula

wherein R¹ to R⁴ and X are as described below, or to pharmaceuticallyacceptable salts thereof.

The compounds are TLR agonists. In particular, the compounds are TLR7and/or TLR8 agonists and more particularly agonists of both TLR7 andTLR8 receptors. Thus, they may be useful for the treatment andprevention of cancer, autoimmune and infectious diseases. For example,they may be useful in a vaccination against diseases such as cancer,autoimmune or infectious diseases.

BACKGROUND OF THE INVENTION

Toll-like receptors (TLRs) are a family of membrane-spanning receptorsthat are expressed on cells of the immune system like dendritic cells,macrophages, monocytes, T cells, B cells, NK cells and mast cells butalso on endothelial and epithelial cells (Kawai et al., Immunity, 2011,34, 637-650, Kawai et al., Nat. Immunol., 2010, 11, 373-384). TLRs thatrecognize bacterial and fungal components are expressed on the cellsurface (i.e. TLR1, 2, 4, 5 and 6), while others that recognize viral ormicrobial nucleic acids like TLR3, 7, 8 and 9 are localized to theendolysosomal/phagosomal membrane (Henessy et al. Nat. Rev. DrugDiscovery 2010, 9, 293-307). TLR activation leads to the induction andrelease of pro-inflammatory cytokines, with the specific activationsequence and response depending on the specific TLR and cell type. TLR7and TLR8 are both expressed in monocytes and macrophages, with TLR7 alsohighly expressed in plasmacytoid dendritic cells and TLR8 in myeloiddendritic cells and mast cells. Both receptors are activated by ssRNAand their activation stimulates the production of cytokines such asIL-6, IL-12, TNF-α and IFN-γ and additional co-stimulatory molecules andchemokine receptors. Dependent on the cell type, type I interferons,IFNa (from plasmacytoid dendritic cells) and IFNβ, are also produced bycells upon activation with TLR7/8 agonists (Uematsu et al., J. Biol.Chem., 2007, 282, 15319-15323).

Small molecule agonists for both the TLR7 and TLR8 receptor as well asanalogs modified for use as vaccine adjuvants or conjugates have beenidentified in many patents (i.e. WO1992015582, US 2003187016, WO2005076783, WO2007024612, WO2009111337, WO2010093436, WO2011017611,WO2011068233, WO2011139348, WO2012066336, WO2012167081, WO2013033345, WO2013067597, WO2013166110, and US2013202629). Clinical experience hasbeen obtained using exclusively TLR7 agonists. A number of the earlycompounds have demonstrated anti-viral and anti-cancer properties. Forexample, the TLR7 agonist imiquimod (ALDARA™) was approved by the U.S.Food and Drug Administration as a topical agent for the treatment ofgenital warts, superficial basal cell carcinoma and actinic keratosis.Systemic application however of the early TLR7 agonists like resiquimodhas been abandoned due to intolerable cardiotoxicity observed uponglobal chemokine stimulation at therapeutic levels (Holldack, DrugDiscovery Today, 2013, 1-4). Knowledge about TLR8 agonists is lessadvanced and mostly restricted to data with early mixed TLR7/8 agonistslike resiquimod and more recently to compounds described by VentiRXPharmaceuticals (i.e. WO2010054215, WO2012045090). At present there isstill a need for additional small molecule TLR7 and TLR8 agonists,specifically those with improved potency.

The present invention is directed to1H-imidazo[4,5-c]quinolin-4-amine-2-methylpropan-2-yloxy derivativeswith improved cellular potency over known TLR7 and/or TLR8 agonists ofthis type for use in the treatment of cancer, preferably solid tumorsand lymphomas, and for other uses including the treatment of certainskin conditions or diseases, such as atopic dermatitis, the treatment ofinfectious diseases, preferably viral diseases, and for use as adjuvantsin vaccines formulated for use in cancer therapy or by desensitizing ofthe receptors by continuous stimulation in the treatment of autoimmunediseases.

Specifically, the present invention discloses1H-imidazo[4,5-c]quinolin-4-amine-2-methylpropan-2-yloxy derivativesthat are derivatized directly on the tertiary alcohol with an aminoethylor glycine moiety. Due to the poor reactivity of the tertiary alcoholthese derivatives had obviously eluded earlier attempts at synthesis.Surprisingly, these new compounds possess high cellular potency at TLR7that is comparable or even better than resiquimod itself, whereas closeanalogs that have been described earlier such as1-(2-(2-Aminoethoxy)ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(Example 69 of US20030187016) do not show the required activity. Inaddition and also surprisingly, the described1H-imidazo[4,5-c]quinolin-4-amine-2-methylpropan-2-yloxy derivatives arestrong TLR8 receptor agonists with potency comparable or superior to sofar disclosed TLR8 agonists from other chemical classes and muchimproved over resiquimod itself. Thus, the compounds of the presentinvention fulfil the need of activating both TLR7 and TLR8 receptorswith improved potency.

SUMMARY OF THE INVENTION

The present invention relates to 4-amino-imidazoquinoline derivatives ofthe formula

wherein

-   R¹ is C₁₋₇-alkyl or C₁₋₇-alkoxy-C₁₋₇-alkyl;-   R² is selected from the group consisting of hydrogen, halogen,    hydroxyl, hydroxy-C₁₋₇-alkyl, alkoxy-C₁₋₇-alkyl, carboxyl,    carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl,    aminocarbonyl-C₁₋₇-alkyl, aminocarbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl,    C₁₋₇-alkylamino-carbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkyl-sulfonyl-C₁₋₇-alkyl, sulfamoyl-C₁₋₇-alkyl,    C₁₋₇-alkyl-sulfamoyl-C₁₋₇-alkyl,    -   phenyl, said phenyl being unsubstituted or substituted with one,        two or three groups selected from the group consisting of        C₁₋₇-alkyl, C₁₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,        halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy,        cyano, carboxyl, C₁₋₇-alkoxycarbonyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl,        hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,        carboxyl-C₁₋₇-alkylsulfonyl,        C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,        di-C₁₋₇-alkylamino and nitro, and    -   phenoxy, said phenoxy group being unsubstituted or substituted        with one, two or three groups selected from the group consisting        of C₁₋₇-alkyl, C₁₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,        halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy,        cyano, carboxyl, C₁₋₇-alkoxycarbonyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkyl-sulfonyl,        hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,        carboxyl-C₁₋₇-alkylsulfonyl,        C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,        di-C₁₋₇-alkylamino and nitro;-   R³ is hydrogen or halogen;-   R⁴ is selected from the group consisting of    -   —O—(CH₂)_(m)—NHR⁵, and    -   —O—(CO)—(CH₂)_(n)—NHR⁶,    -   wherein    -   m is selected from 1, 2 or 3,    -   n is selected from 1 or 2,    -   R⁵ is selected from the group consisting of hydrogen,        hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,        phenylcarbonyl, heteroarylcarbonyl, carboxyl,        carboxyl-C₁₋₇-alkyl and        C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl, and    -   R⁶ is selected from the group consisting of hydrogen,        hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,        phenylcarbonyl, heteroarylcarbonyl, carboxyl,        carboxyl-C₁₋₇-alkyl and        C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl,        or pharmaceutically acceptable salts thereof.

The invention is also concerned with processes for the manufacture ofcompounds of formula I.

The invention also relates to pharmaceutical compositions comprising acompound of formula I as described above and a pharmaceuticallyacceptable carrier and/or adjuvant.

A further aspect of the invention is the use of compounds of formula Ias therapeutic active substances for the treatment of diseases that canbe mediated with TLR agonists, in particular

TLR7 and/or TLR8 agonists, more particularly TLR7 and TLR8 receptors.The invention thus relates to a method for the treatment of a diseasethat can be mediated with TLR agonists such as for example cancer andautoimmune or infectious diseases.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Furthermore, the followingdefinitions are set forth to illustrate and define the meaning and scopeof the various terms used to describe the invention.

The nomenclature used in this application is based on IUPAC systematicnomenclature, unless indicated otherwise.

The term “compound(s) of this invention” and “compound(s) of the presentinvention” refers to compounds of formula I and solvates or saltsthereof (e.g., pharmaceutically acceptable salts).

The term “substituent” denotes an atom or a group of atoms replacing ahydrogen atom on the parent molecule.

The term “halogen” refers to fluoro, chloro, bromo and iodo, withfluoro, chloro and bromo being of particular interest. Moreparticularly, halogen refers to fluoro and chloro.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, particularly one to sixteencarbon atoms, more particularly one to ten carbon atoms. The term“C₁₋₁₀-alkyl” refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to ten carbon atoms, suchas e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 1,1,3,3-tetramethyl-butyl and the like. Moreparticularly, the term “alkyl” also embraces lower alkyl groups asdescribed below.

The term “lower alkyl” or “C₁₋₇-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 7carbon atoms, in particular a straight or branched-chain alkyl groupwith 1 to 6 carbon atoms and more particularly a straight orbranched-chain alkyl group with 1 to 4 carbon atoms. Examples ofstraight-chain and branched C₁₋₇ alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, theisomeric hexyls and the isomeric heptyls, in particular methyl andethyl.

The term “lower alkenyl” or “C₂₋₇-alkenyl” signifies a straight-chain orbranched chain hydrocarbon residue comprising an olefinic bond and 2 to7, in particular 3 to 6, more particularly 3 to 4 carbon atoms. Examplesof alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl and isobutenyl, in particular ethenyl.

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” denotes a saturatedmonocyclic hydrocarbon group containing from 3 to 7 carbon atoms, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, moreparticularly cyclopropyl. In addition, the term “cycloalkyl” alsoembraces bicyclic hydrocarbon groups containing from 3 to 10 carbonatoms. Bicyclic means a cycloalkyl group consisting of two saturatedcarbocycles having one or more carbon atoms in common. Examples forbicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.

The term “lower alkoxy” or “C₁₋₇-alkoxy” refers to the group R′—O—,wherein R′ is lower alkyl and the term “lower alkyl” has the previouslygiven significance. Examples of lower alkoxy groups are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert-butoxy,in particular methoxy.

The term “lower alkoxyalkyl” or “C₁₋₇-alkoxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a lower alkoxy group. Among thelower alkoxyalkyl groups of particular interest are methoxymethyl,2-methoxyethyl and 2-ethoxyethyl, with 2-ethoxyethyl being of mostparticular interest.

The term hydroxy or hydroxyl means the group —OH.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Among theparticular interesting lower hydroxyalkyl groups are hydroxymethyl orhydroxyethyl.

The term “lower halogenalkyl” or “halogen-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a halogen atom, particularlyfluoro or chloro, most particularly fluoro. Among the lower halogenalkylgroups of particular interest are trifluoromethyl, difluoromethyl,trifluoroethyl, 2,2-difluoroethyl, fluoromethyl and chloromethyl, withtrifluoromethyl being of more particular interest.

The term “lower halogenalkoxy” or “halogen-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,particularly fluoro or chloro, most particularly fluoro. Among the lowerhalogenalkoxy groups of particular interest are trifluoromethoxy,difluoromethoxy, fluormethoxy and chloromethoxy, more particularlytrifluoromethoxy.

The term “carboxyl” means the group —COOH.

The term “lower carboxylalkyl” or “carboxyl-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a carboxyl group. Among thelower carboxylalkyl groups or particular interest are carboxylmethyl(—CH₂—COOH) and carboxylethyl (—CH₂—CH₂—COOH).

The term “lower alkoxycarbonyl” or “C₁₋₇-alkoxycarbonyl” refers to thegroup —COOR, wherein R is lower alkyl and the term “lower alkyl” has thepreviously given significance. Lower alkoxycarbonyl groups of particularinterest are methoxycarbonyl or ethoxycarbonyl.

The term “lower alkoxycarbonylalkyl” or “C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl”means lower alkyl groups as defined above wherein one of the hydrogenatoms of the lower alkyl group is replaced by C₁₋₇-alkoxycarbonyl. Aparticular lower alkoxycarbonylalkyl group is —CH₂—COOCH₃.

The term “lower alkylcarbonyl” or “C₁₋₇-alkylcarbonyl” means the group—C(O)—R, wherein R is a lower alkyl group as defined above. A loweralkylcarbonyl group of particular interest is methylcarbonyl or acetyl.

The term “lower alkoxycarbonylalkyl” or “C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl”refers to lower alkyl groups as defined above wherein at least one ofthe hydrogen atoms of the lower alkyl group is replaced by a loweralkoxycarbonyl group. Among the particular interesting loweralkoxycarbonyl-alkyl groups is —(CH₂)₂—COOC₂H₅.

The term “lower alkoxycarbonylalkenyl” or“C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl” refers to lower alkenyl groups asdefined above wherein at least one of the hydrogen atoms of the loweralkenyl group is replaced by a lower alkoxycarbonyl group. Among theparticular interesting lower alkoxycarbonyl-alkenyl groups is—(CH₂)₂—COOC₂H₅.

The term “lower alkylsulfonyl” or “C₁₋₇-alkylsulfonyl” means the group—S(O)₂—R, wherein R is a lower alkyl group as defined above. A loweralkylsulfonyl group of particular interest is methylsulfonyl.

The term “lower alkylsulfonylalkyl” or “C₁₋₇-alkylsulfonyl-C₁₋₇-alkyl”means lower alkyl groups as defined above wherein one of the hydrogenatoms of the lower alkyl group is replaced by C₁₋₇-alkylsulfonyl. Aparticular lower alkylsulfonylalkyl group is —CH₂—S(O)₂—CH₃.

The term “lower hydroxyalkylsulfonyl” or “hydroxy-C₁₋₇-alkylsulfonyl”refers to lower alkylsulfonyl groups as defined above wherein at leastone of the hydrogen atoms of the lower alkylsulfonyl group is replacedby a hydroxy group. Among the particular interesting lowerhydroxyalkylsulfonyl groups are hydroxyethylsulfonyl.

The term “lower alkoxyalkylsulfonyl” or “C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl”refers to lower alkylsulfonyl groups as defined above wherein at leastone of the hydrogen atoms of the lower alkylsulfonyl group is replacedby a lower alkoxy group. Among the particular interesting loweralkoxyalkylsulfonyl groups are methoxyethylsulfonyl orethoxyethylsulfonyl.

The term “lower alkoxycarbonylalkylsulfonyl” or“C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-sulfonyl” refers to lower alkylsulfonylgroups as defined above wherein at least one of the hydrogen atoms ofthe lower alkylsulfonyl group is replaced by a lower alkoxycarbonylgroup. Among the particular interesting loweralkoxycarbonyl-alkylsulfonyl groups is —S(O)₂—(CH₂)₂—COOCH₃.

The term “carboxylalkylsulfonyl” or “carboxyl-C₁₋₇-alkylsulfonyl” refersto lower alkylsulfonyl groups as defined above wherein at least one ofthe hydrogen atoms of the lower alkylsulfonyl group is replaced by acarboxyl group. Among the particular interesting lowercarboxyl-alkylsulfonyl groups are —S(O)₂—(CH₂)₃—COOH or—S(O)₂—(CH₂)₄—COOH.

The term “sulfamoyl” or “aminosulfonyl” means the group —S(O)₂—NH₂.

The term “lower alkylsulfamoyl” or “C₁₋₇-alkyl-sulfamoyl” defines thegroup —S(O)₂—NH—R, wherein R is lower alkyl and the term “lower alkyl”has the previously given meaning An example of a lower alkylsulfamoylgroup is methylsulfamoyl (methylaminosulfonyl).

The term “lower sulfamoylalkyl” or “sulfamoyl-C₁₋₇-alkyl” defines alower alkyl group as defined above wherein one of the hydrogen atoms ofthe lower alkyl group is replaced by the group —S(O)₂—NH₂.

The term “lower alkylsulfamoylalkyl” or “C₁₋₇-alkyl-sulfamoylalkyl”defines a lower alkyl group as defined above wherein one of the hydrogenatoms of the lower alkyl group is replaced by the group —S(O)₂—NH—R,wherein R is lower alkyl and the term “lower alkyl” has the previouslygiven meaning

“Amino” refers to the group —NH₂. The term “C₁₋₇-alkylamino” means agroup —NHR, wherein R is lower alkyl and the term “lower alkyl” has thepreviously given significance. The term “di-C₁₋₇-alkylamino” means agroup —NRR′, wherein R and R′ are lower alkyl groups as defined above.

The term “lower aminoalkyl” or “amino-C₁₋₇-alkyl” refers to lower alkylgroups as defined above wherein at least one of the hydrogen atoms ofthe lower alkyl group is replaced by an amino group. Among theparticular interesting lower aminoalkyl groups are aminomethyl or2-aminoethyl.

The term “aminocarbonyl” refers to the group —CO—NH₂.

The term “lower aminoalkylcarbonyl” or “amino-C₁₋₇-alkyl-carbonyl”refers to the group —CO—R″, wherein R″ is a lower aminoalkyl group asdefined herein before.

The term “lower aminocarbonylalkyl” or “aminocarbonyl-C₁₋₇-alkyl” meanslower alkyl groups as defined above wherein one of the hydrogen atoms ofthe lower alkyl group is replaced by aminocarbonyl. A loweraminoarbonylalkyl group of particular interest is —CH₂—CONH₂.

The term “lower alkylaminocarbonylalkyl” or“C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl” refers to a lower alkyl group asdefined above wherein one of the hydrogen atoms of the lower alkyl groupis replaced by a group —CONH—R, wherein R is lower alkyl as definedherein before.

C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl

The term “lower alkoxycarbonylaminoalkylcarbonyl” or“C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl” refers to loweraminoalkylcarbonyl groups as defined above wherein at least one of thehydrogen atoms of the amino group is replaced by a lower alkoxycarbonylgroup. Among the particular interesting loweralkoxycarbonyl-alkylsulfonyl groups is —CO—(CH₂)₅—NH—COOC(CH₃)₃.

The term “cyano” refers to the group —CN.

The term “nitro” refers to the group —NO₂.

The term “phenylcarbonyl” means the group —CO-Phe, wherein Phe standsfor an optionally substituted phenyl group.

The term “heteroaryl” in general refers to an aromatic 5- or 6-memberedring which comprises one, two, three or four atoms selected fromnitrogen, oxygen and/or sulfur, such as pyridyl, pyrazinyl, pyrimidinyl,2,4-dioxo-1H-pyrimidinyl, pyridazinyl, 2-oxo-1,2-dihydropyridinyl,pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, tetrazolyl,pyrazolyl, imidazolyl, furanyl, thiazolyl, isothiazolyl, triazolyl,tetrazolyl, thienyl, azepinyl, diazepinyl. The term “heteroaryl” furtherrefers to bicyclic aromatic groups comprising from 5 to 12 ring atoms,in which one or both rings can contain one, two or three atoms selectedfrom nitrogen, oxygen or sulfur, such as quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl,quinoxalinyl, benzofuranyl, benzothienyl, benzothiazolyl,benzotriazolyl, indolyl and indazolyl. More particularly, “heteroaryl”refers to an aromatic 6-membered ring selected from the group consistingof pyridyl, pyrazinyl pyrimidinyl and pyridazinyl, more particularlypyridyl.

The term “oxo” means that a C-atom of the heteroaryl ring may besubstituted by ═O, thus meaning that the heteroaryl ring may contain oneor more carbonyl (—CO—) groups.

The term “heteroarylcarbonyl” means the group —CO-Het, wherein Het is anoptionally substituted heteroaryl group as defined above.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

Compounds of formula I can form pharmaceutically acceptable salts. Theterm “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable.Pharmaceutically acceptable salts include both acid and base additionsalts. The salts are for example acid addition salts of compounds offormula I with physiologically compatible mineral acids, such ashydrochloric acid, hydrobromic acid, nitric acid, carbonic acid,sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids,such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonicacid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, lactic acid, trifluoroacetic acid, citric acid,fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid,cinnamic acid, mandelic acid, embonic acid, succinic acid or salicylicacid. In addition, pharmaceutically acceptable salts may be preparedfrom addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium, zinc,copper, manganese and aluminium salts and the like. Salts derived fromorganic bases include, but are not limited to salts of primary,secondary, and tertiary amines, substituted amines including naturallyoccurring substituted amines, cyclic amines and basic ion exchangeresins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, lysine, arginine,histidine, caffeine, procaine, hydrabamine, choline, betaine,ethylendiamine, glucosamine, methylglucamine, theobromine, piperazine,N-ethylpiperidine, piperidine and polyamine resins. The compound offormula I can also be present in the form of zwitterions.Pharmaceutically acceptable salts of compounds of formula I ofparticular interest are the sodium salts or salts with tertiary amines.

The compounds of formula I can also be solvated, e.g., hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The term“pharmaceutically acceptable salts” also includes physiologicallyacceptable solvates.

The term “agonist” denotes a compound that enhances the activity ofanother compound or receptor site as defined e.g. in Goodman andGilman's “The Pharmacological Basis of Therapeutics, 7th ed.” in page35, Macmillan Publ. Company, Canada, 1985. A “full agonist” effects afull response whereas a “partial agonist” effects less than fullactivation even when occupying the total receptor population. An“inverse agonist” produces an effect opposite to that of an agonist, yetbinds to the same receptor binding-site.

The term “half maximal effective concentration” (EC₅₀) denotes theplasma concentration of a particular compound required for obtaining 50%of the maximum of a particular effect in vivo.

The term “therapeutically effective amount” denotes an amount of acompound of the present invention that, when administered to a subject,(i) treats or prevents the particular disease, condition or disorder,(ii) attenuates, ameliorates or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, conditionor disorder described herein. The therapeutically effective amount willvary depending on the compound, disease state being treated, theseverity or the disease treated, the age and relative health of thesubject, the route and form of administration, the judgment of theattending medical or veterinary practitioner, and other factors.

In detail, the present invention relates to compounds of the formula

-   wherein-   R¹ is C₁₋₇-alkyl or C₁₋₇-alkoxy-C₁₋₇-alkyl;-   R² is selected from the group consisting of hydrogen, halogen,    hydroxyl, hydroxy-C₁₋₇-alkyl, alkoxy-C₁₋₇-alkyl, carboxyl,    carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl,    aminocarbonyl-C₁₋₇-alkyl, aminocarbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl,    C₁₋₇-alkylamino-carbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkyl-sulfonyl-C₁₋₇-alkyl, sulfamoyl-C_(1-7—)alkyl,    C₁₋₇-alkyl-sulfamoyl-C₁₋₇-alkyl,    -   phenyl, said phenyl being unsubstituted or substituted with one,        two or three groups selected from the group consisting of        C₁₋₇-alkyl, C₁₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,        halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy,        cyano, carboxyl, C₁₋₇-alkoxycarbonyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl,        hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,        carboxyl-C₁₋₇-alkylsulfonyl,        C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,        di-C₁₋₇-alkylamino and nitro, and    -   phenoxy, said phenoxy group being unsubstituted or substituted        with one, two or three groups selected from the group consisting        of C₁₋₇-alkyl, C₁₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,        halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy,        cyano, carboxyl, C₁₋₇-alkoxycarbonyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkyl-sulfonyl,        hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,        carboxyl-C₁₋₇-alkylsulfonyl,        C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,        di-C₁₋₇-alkylamino and nitro;-   R³ is hydrogen or halogen;-   R⁴ is selected from the group consisting of    -   —O—(CH₂)_(m)—NHR⁵, and    -   —O—(CO)—(CH₂)_(n)—NHR⁶,    -   wherein    -   m is selected from 1, 2 or 3,    -   n is selected from 1 or 2,    -   R⁵ is selected from the group consisting of hydrogen,        hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,        phenylcarbonyl, heteroarylcarbonyl, carboxyl,        carboxyl-C₁₋₇-alkyl and        C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl, and    -   R⁶ is selected from the group consisting of hydrogen,        hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,        phenylcarbonyl, heteroarylcarbonyl, carboxyl,        carboxyl-C₁₋₇-alkyl and        C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl,-   or pharmaceutically acceptable salts thereof.

In a particular aspect, the present invention relates to compounds ofthe formula

-   wherein-   R¹ is C₁₋₇-alkyl or C₁₋₇-alkoxy-C₁₋₇-alkyl;-   R² is selected from the group consisting of hydrogen, hydroxyl,    hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, carboxyl,    carboxyl-C₁₋₇-alkyl, aminocarbonyl-C₁₋₇-alkyl,    C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl, alkoxycarbonyl-C₁₋₇-alkyl,    C₁₋₇-alkyl-sulfonyl-C₁₋₇-alkyl, sulfamoyl-C_(1-7—)alkyl,    C₁₋₇-alkyl-sulfamoyl-C₁₋₇-alkyl,    -   phenyl, said phenyl being unsubstituted or substituted with one,        two or three groups selected from the group consisting of        C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,        halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy,        cyano, carboxyl, C₁₋₇-alkoxycarbonyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl,        hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,        carboxyl-C₁₋₇-alkylsulfonyl,        C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,        di-C₁₋₇-alkylamino and nitro, and    -   phenoxy, said phenoxy group being unsubstituted or substituted        with one, two or three groups selected from the group consisting        of C₁₋₇-alkyl, C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,        halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy,        cyano, carboxyl, C₁₋₇-alkoxycarbonyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkyl-sulfonyl,        hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,        carboxyl-C₁₋₇-alkylsulfonyl,        C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,        di-C₁₋₇-alkylamino and nitro;-   R³ is hydrogen or halogen;-   R⁴ is selected from the group consisting of    -   —O—(CH₂)_(m)—NHR⁵, and    -   —O—(CO)—(CH₂)_(n)—NHR⁶,    -   wherein    -   m is selected from 1, 2 or 3,    -   n is selected from 1 or 2,    -   R⁵ is selected from the group consisting of hydrogen,        hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,        phenylcarbonyl, heteroarylcarbonyl, carboxyl, and        carboxyl-C₁₋₇-alkyl, and    -   R⁶ is selected from the group consisting of hydrogen,        hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,        phenylcarbonyl, heteroarylcarbonyl, carboxyl, and        carboxyl-C₁₋₇-alkyl,-   or pharmaceutically acceptable salts thereof.

In one aspect, the invention relates to compounds of formula I, whereinR¹ is C₁₋₇-alkoxy-C₁₋₇-alkyl. More particularly, R¹ is ethoxyethyl.

In another aspect, the invention refers to compounds of formula I,wherein R³ is hydrogen.

In a further aspect, the invention relates to compounds of formula I,wherein R⁴ is —O—(CH₂)_(m)—NHR⁵ and wherein m is selected from 1, 2 or 3and wherein R⁵ is selected from the group consisting of hydrogen,hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C₁₋₇-alkyl andC₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl. In particular, theinvention refers to compounds of formula I, wherein R⁴ is—O—(CH₂)_(m)—NHR⁵ and wherein m is selected from 1, 2 or 3 and whereinR⁵ is selected from the group consisting of hydrogen,hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,phenylcarbonyl, heteroarylcarbonyl, carboxyl, and carboxyl-C₁₋₇-alkyl.

In particular, the invention relates to compounds of formula I, whereinR⁴ is —O—(CH₂)_(m)—NHR⁵ and wherein m is 2 and R⁵ is as defined hereinbefore.

More particularly, the invention relates to compounds of formula I,wherein R⁴ is —O—(CH₂)_(m)—NHR⁵ and wherein m is 2 and wherein R⁵ isselected from the group consisting of hydrogen, hydroxy-C₁₋₇-alkyl,C₁₋₇-alkylcarbonyl, heteroarylcarbonyl andC₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl, more particularly whereinR⁵ is selected from the group consisting of hydrogen,hydroxy-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl andC₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl. Most particularly, theinvention refers to a compound of formula I, wherein R⁴ is—O—(CH₂)_(m)—NHR⁵ and wherein m is 2 and R⁵ is hydrogen.

The invention also relates to compounds of formula I, wherein R⁴ is—O—(CH₂)_(m)—NHR⁵ and wherein m is selected from 1, 2 or 3 and whereinR⁵ is selected from the group consisting of hydrogen,hydroxy-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl and heteroarylcarbonyl. Moreparticularly, the invention refers to compounds of formula I, wherein R⁴is —O—(CH₂)_(m)—NHR⁵ and wherein m is selected from 1, 2 or 3 andwherein R⁵ is hydrogen.

In another aspect, the invention refers to compounds of formula I,wherein R⁴ is —O—(CO)—(CH₂)_(n)—NHR⁶ and wherein n is selected from 1 or2 and wherein R⁶ is selected from the group consisting of hydrogen,hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C₁₋₇-alkyl andC₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl.

In particular, the invention refers to compounds of formula I, whereinR⁴ is —O—(CO)—(CH₂)_(n)—NHR⁶ and wherein n is 1 or 2 and wherein R⁶ isas defined herein before. More particularly, the invention relates tocompounds of formula I, wherein R⁴ is —O—(CO)—(CH₂)_(n)—NHR⁶ and whereinn is 1 and R⁶ is hydrogen.

In a further aspect, the invention also relates to compounds of formulaI, wherein R⁴ is —O—(CO)—(CH₂)_(n)—NHR⁶ and wherein n is 1 or 2 andwherein R⁶ is hydrogen.

The invention also relates to compounds of formula I, wherein R² isselected from the group consisting of hydrogen, halogen, hydroxyl,hydroxy-C₁₋₇-alkyl, alkoxy-C₁₋₇-alkyl, carboxyl, carboxyl-C₁₋₇-alkyl,carboxyl-C₂₋₇-alkenyl, aminocarbonyl-C₁₋₇-alkyl,aminocarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl,C₁₋₇-alkylamino-carbonyl-C₂₋₇-alkenyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkyl-sulfonyl-C₁₋₇-alkyl,sulfamoyl-C_(1-7—)alkyl and C₁₋₇-alkyl-sulfamoyl-C₁₋₇-alkyl.

In another aspect, the invention relates to compounds of formula I,wherein R² is selected from the group consisting of hydrogen, halogen,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl and C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl.

In a particular aspect, the invention relates to compounds of formula I,wherein R² is hydrogen.

In another aspect, the invention relates to compounds of formula I,wherein R² is phenyl, said phenyl being unsubstituted or substitutedwith one, two or three groups selected from the group consisting ofC₁₋₇-alkyl, C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy, cyano,carboxyl, C₁₋₇-alkoxycarbonyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkylsulfonyl, hydroxy-C₁₋₇-alkylsulfonyl,C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl, carboxyl-C₁₋₇-alkylsulfonyl,C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,di-C₁₋₇-alkylamino and nitro, or to compounds of formula I, wherein R²is phenoxy, said phenoxy group being unsubstituted or substituted withone, two or three groups selected from the group consisting ofC₁₋₇-alkyl, C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl,halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy, cyano,carboxyl, C₁₋₇-alkoxycarbonyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkyl-sulfonyl, hydroxy-C₁₋₇-alkylsulfonyl,C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl, carboxyl-C₁₋₇-alkylsulfonyl,C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,di-C₁₋₇-alkylamino and nitro.

Particular compounds of formula I according to the invention are thefollowing:

-   1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,-   1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl    2-aminoacetate,-   N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)nicotinamide,-   N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)acetamide,-   3-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)propan-1-ol,-   tert-butyl    6-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)-6-oxohexylcarbamate,-   ethyl    (E)-3-[4-amino-1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate,-   ethyl    3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,-   ethyl    3-(4-amino-1-(2-(2-aminoacetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,-   1-(2-(2-aminoethoxy)-2-methylpropyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine,-   1-(2-(2-aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,-   or pharmaceutically acceptable salts thereof.

Particularly, the invention relates to the following compounds offormula I:

-   1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,-   1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl    2-aminoacetate,-   ethyl    3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,-   or pharmaceutically acceptable salts thereof.

More particularly, the invention relates to a compound of formula I,which is

-   1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,-   and pharmaceutically acceptable salts thereof.

More particularly, the invention relates to compounds of formula Iselected from the group consisting of

-   1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl    2-aminoacetate,-   ethyl    3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,-   and pharmaceutically acceptable salts thereof.

In particular, the invention refers to the following salts of compoundsof formula I:

-   ethyl    3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate    hydrochloride,-   1-(2-(2-aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,-   or pharmaceutically acceptable salts thereof.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises

a) reacting an compound of the formula II

wherein R¹, R² and R³ are as defined hereinbefore and PG is a protectinggroup, with a compound of the formula III

wherein m is as defined herein before, under basic conditions andremoving the protecting groups PG and Boc under acidic conditions toobtain a compound of the formula I-a

wherein R¹ to R³ and m are as defined herein before, and optionallyfurther coupling the compound of formula I-a with an alcohol or acid ofthe formula R⁵—OH or and aldehyde of the formula R⁵═O to obtain acompound of formula I-c

wherein R¹ to R³, m and R⁵ are as defined herein before, and, ifdesired, converting the compound obtained into a pharmaceuticallyacceptable salt, or

b) reacting an compound of the formula II-a

wherein R¹, R² and R³ are as defined herein before and PG′ is aprotecting group, with a carboxylic acid of the formula IV

wherein n is defined as herein before and PG″ is a protecting group, inthe presence of a esterification agent and removing the protectinggroups PG′ and PG″ with a mild reducing agent to obtain a compound ofthe formula I-b

wherein R¹ to R³ and n are as defined herein before, and optionallyfurther coupling the compound of formula I-a with an alcohol or acid ofthe formula R⁶—OH or and aldehyde of the formula R⁶═O to obtain acompound of formula I-d

wherein R¹ to R³, m and R⁶ are as defined herein before, and, ifdesired, converting the compound obtained into a pharmaceuticallyacceptable salt.

In particular, a suitable protecting group PG is an amino-protectinggroup selected from trityl (TRT), or double protection by using anisoindoline-1,3-dione, bis-benzyl or bis-carboxybenzyl (bis-Z)protecting group.

“Under basic conditions” means the presence of a base such as sodiumhydride or potassium tert-butylate. The reaction is carried out in asuitable solvent such as for example N,N-dimethylformamide (DMF),dimethylacetamide (DMA), dichloromethane or dioxane, at temperaturesbetween 0° C. and room temperature.

“Removing the protecting groups PG and Boc under acidic conditions”means treating the protected compound with acids in a suitable solvent,for instance trifluoroacetic acid (TFA) in a solvent such asdichloromethane (DCM) can be employed.

Suitable protecting groups PG′ and PG″ are protecting groups that form acyclic ring with the nitrogen atom of the amino group. In particular,PG′ or PG″ together with the nitrogen atom they are attached to, form anisoindoline-1,3-dione or signify a bis-benzyl or bis-carboxybenzylprotecting group.

An esterification agent is a compound that facilitates an esterificationreaction. A particular esterification agent isN,N-diisopropyl-carbodiimide. The reaction is particularly carried outin an inert solvent, such as DCM.

“Removing the protecting groups PG′ and PG″ with a mild reducing agent”means in particular treating the protected compound with hydrazine/waterin an inert solvent, such as THF.

The invention further relates to compounds of formula I as defined aboveobtainable according to a process as defined above.

The synthesis of the compounds with the general structure I can, forexample, be accomplished according to the following schemes. Unlessotherwise indicated, R¹ to R³ and X are as defined above.

An access route to starting materials of formula AG is given in Scheme1, and the route has been exemplified in WO 2013/033345 (Univ. ofMinnesota).

Compounds AB can be obtained from suitably substituted orthoesters AA bycondensation with 2-amino-propanedinitrile and1-amino-2-methyl-propan-2-ol in an inert solvent, as for example THF inthe presence of a base, like for example triethylamine. Suitablesubstituted orthoesters AA are commercially available, can besynthesized by a person skilled in the art or have been exemplified inthe experimental part.

Compounds AC can be obtained from compounds AB bydiazotization/iodination as known in the art; specifically by usingdiiodomethane as iodide source and isoamylnitrite as nitrite source inan inert solvent like chloroform at temperatures from 0° C. to theboiling temperature of the solvent, preferably at a temperature of 80°C.

Compounds of formula AC can be coupled with compounds of formula ADwhere M denotes a metal leaving group and R′ denotes a hydrogen and/or asuitable protecting group, by methods known in the art, to givecompounds of formula AE. Suitable metal leaving groups may be boronicacids, boronate esters, and trifluoroborates but also tin or zinc basedleaving groups. In particular boronic acids or boronate esters can beused in Suzuki-Miyaura type couplings using a palladium catalyst, likePd(OAc)₂ in the presence of triphenylphosphine, in an inert solvent,like DME, together with a suitable base, like sodium carbonate. Thereaction temperature may range from room temperature to the boilingtemperature of the solvent, with room temperature being a suitablechoice in many cases.

If compounds AE are protected at the aniline amino group (one R′ unequalH), deprotection to yield compounds of type AF can be done by methodsknown in the art, with acidic cleavage of the protecting group using TFAbeing a preferred choice.

Compounds of type AG can be obtained from compounds AF by thermalcondensation (ring closure) in the presence of an acid catalyst. Thiscan simply be achieved by heating compounds AF in an inert solvent, likedioxane, in the presence of an acid, like HCl, for an appropriate time,for example for 2 hours at 90° C.

Following the procedure according to scheme 2, compounds AG can be usedas starting material for the synthesis of compounds I-a where R⁴ is—O—(CH₂)_(m)—NH₂.

Compound BA can be obtained from AG by reaction with tritylchloride inthe presence of a base in an inert solvent at elevated temperature withor without microwave irradiation. A suitable base-solvent combinationis, for example, triethylamine or DIEA and acetonitrile, especially ifthe reaction is performed at elevated temperature in a microwavereactor.

Compounds of the general formula BC can be obtained from compounds ofthe general formula BA by reaction with the Boc-sulfamidate BB in asuitable solvent like DMF in the presence of a suitable base like sodiumhydride of potassium tert-butylate. The reaction is advantageouslyperformed at 0° C. to room temperature.

Compounds of the general formula I-a can be obtained from compounds ofthe general formula BC by removal of the protecting groups by treatmentwith acids in a suitable solvent. One such acid is TFA with or withoutadditional DCM, used at room temperature.

Following the procedure according to scheme 3, compound AG can be usedas starting material for the synthesis of compounds I-b where R⁴ is—O—(CO)—(CH₂)_(n)—NH₂.

Compound CA can be obtained from AG by introduction of a suitableprotecting group PG by methods known in the art. Such protecting groupsmay be for example the isoindoline-1,3-dione (phtalyl). Specifically,compound CA can be reacted with phtaloylchloride in the presence of abase, like 1,4-diazabicyclo[2,2,2]octane, in an inert, high boilingsolvent such as toluene, at elevated temperatures to give a compound oftype CA with isoindoline-1,3-dione as protecting group.

Compound CC can be obtained from compounds CB and CA by esterificationusing one of the many methods described in the art. Advantageously, suchesterification can be accomplished by combining CB and CA in an inertsolvent, like DCM, in the presence of N,N-diisopropyl-carbodiimide atelevated temperature. Suitable carboxylic acids CB are commerciallyavailable, can be prepared by procedures known in the art, or have beenexemplified in the experimental part.

Compounds of the general formula I-b can be obtained from compounds ofthe general formula CC by removal of the protecting groups with methodsknown in the art. Specifically, the isoindoline-1,3-dione can be removedby treatment with hydrazine/water in an inert solvent, like THF, at roomtemperature.

Following the procedure according to scheme 4, compounds I-c and I-d canbe obtained from I-a or I-b by methods known in the art, as for exampleamide couplings (R⁵—OH or R⁶—OH are acids) or reductive aminations (R⁵═Oor R⁶═O are aldehydes) as explained in more detail in the experimentalpart.

If one of the starting materials, compounds of the formula AA, AD, AG,DA, DB, DC or DD, contains one or more functional groups which are notstable or are reactive under the reaction conditions of one or morereaction steps, appropriate protecting groups (PG) (as described e.g. inT. W. Greene et al., Protective Groups in Organic Chemistry, John Wileyand Sons Inc. New York 1999, 3rd edition) can be introduced before thecritical step applying methods well known in the art. Such protectinggroups can be removed at a later stage of the synthesis using standardmethods known in the art.

If one or more compounds of the formula AA, AD, AG, DA, DB, DC or DDcontain chiral centers, compounds of formula I can be obtained asmixtures of diastereomers or enantiomers, which can be separated bymethods well known in the art, e.g. (chiral) HPLC or crystallization.Racemic compounds can e.g. be separated into their antipodes viadiastereomeric salts by crystallization or by separation of theantipodes by specific chromatographic methods using either a chiraladsorbent or a chiral eluent.

As described herein before, the compounds of formula I of the presentinvention can be used as medicaments for the treatment of diseases whichare mediated by TLR agonists, in particular for the treatment ofdiseases which are mediated by TLR7 and/or TLR8 agonists, moreparticularly for the treatment of diseases which are mediated by TLR7and TL8 agonists.

The compounds defined in the present invention are agonists of TLR7and/or TLR8 receptors in cellular assays in vitro. More particularly,the compounds of the present invention are agonists of both TLR7 andTLR8 receptors. Accordingly, the compounds of the present invention areexpected to be potentially useful agents in the treatment of diseases ormedical conditions that may benefit from the activation of the immunesystem via TLR7 and/or TLR8 agonists, more particularly in the treatmentof diseases or medical conditions that may benefit from the activationof the immune system via both TLR7 and TLR8 receptors. For example, thefollowing diseases and conditions may be treatable with compounds of thepresent invention.

The compounds of formula I of the present invention are useful inoncology, i.e. they may be used in the treatment of common cancersincluding bladder cancer, head and neck cancer, prostate cancer,colorectal cancer, kidney cancer, breast cancer, lung cancer, ovariancancer, cervical cancer, pancreatic cancer, bowel and colon cancer,stomach cancer, thyroid cancer, melanoma, skin and brain tumors andmalignancies affecting the bone marrow such as leukemias andlymphoproliferative systems, such as Hodgkin's and non-Hodgkin'slymphoma; including the prevention and treatment of metastatic cancerand tumor recurrences, and paraneoplastic syndromes.

The compounds of formula I of the present invention are also useful inthe treatment of autoimmune diseases. An “autoimmune disease” is adisease or disorder arising from and directed against an individual'sown tissues or organs or a co-segregate or manifestation thereof orresulting condition therefrom. “Autoimmune disease” can be anorgan-specific disease (i.e., the immune response is specificallydirected against an organ system such as the endocrine system, thehematopoietic system, the skin, the cardiopulmonary system, thegastrointestinal and liver systems, the renal system, the thyroid, theears, the neuromuscular system, the central nervous system, etc.) or asystemic disease which can affect multiple organ systems (for example,systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis,etc.). In a particular aspect, the autoimmune disease is associated withthe skin, muscle tissue, and/or connective tissue.

Particular autoimmune diseases include autoimmune rheumatologicdisorders (such as, for example, rheumatoid arthritis, Sjogren'ssyndrome, scleroderma, lupus such as SLE and lupus nephritis,polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipidantibody syndrome, and psoriatic arthritis), autoimmune gastrointestinaland liver disorders (such as, for example, inflammatory bowel diseases,ulcerative colitis and Crohn's disease), autoimmune gastritis andpernicious anemia, autoimmune hepatitis, primary biliary cirrhosis,primary sclerosing cholangitis, and celiac disease), vasculitis (suchas, for example, ANCA-negative vasculitis and ANCA-associatedvasculitis, including Churg-Strauss vasculitis, Wegener'sgranulomatosis, and microscopic polyangiitis), autoimmune neurologicaldisorders (such as, for example, multiple sclerosis, opsoclonusmyoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson'sdisease, Alzheimer's disease, and autoimmune polyneuropathies), renaldisorders (such as, for example, glomerulonephritis, Goodpasture'ssyndrome, and Berger's disease), autoimmune dermatologic disorders (suchas, for example, psoriasis, urticaria, hives, pemphigus vulgaris,bullous pemphigoid, and cutaneous lupus erythematosus), hematologicdisorders (such as, for example, thrombocytopenic purpura, thromboticthrombocytopenic purpura, post-transfusion purpura, and autoimmunehemolytic anemia), atherosclerosis, uveitis, autoimmune hearing diseases(such as, for example, inner ear disease and hearing loss), Behcet'sdisease, Raynaud's syndrome, organ transplant, and autoimmune endocrinedisorders (such as, for example, diabetic-related autoimmune diseasessuch as insulin-dependent diabetes mellitus (IDDM), Addison's disease,and autoimmune thyroid disease (e.g., Graves' disease and thyroiditis)),allergic conditions and responses, food allergies, drug allergies,insect allergies, rare allergic disorders such as mastocytosis, allergicreaction, eczema including allergic or atopic eczema, asthma such asbronchial asthma and auto-immune asthma, conditions involvinginfiltration of T cells and chronic inflammatory responses:

The compounds of formula I of the present invention are also useful inthe treatment of infectious diseases. Thus, they may be useful in thetreatment of viral diseases, in particular for diseases caused byinfection with viruses selected from the group consisting of papillomaviruses, such as human papilloma virus (HPV) and those that causegenital warts, common warts and plantar warts, herpes simplex virus,molluscum contagiosum, hepatitis B virus (HBV), hepatitis C virus (HCV),Dengue virus, variola virus, human immunodeficiency virus (HIV),cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus,enterovirus, adenovirus, coronavirus (e.g. SARS), influenza, mumps andparainfluenza.

They may also be useful in the treatment of bacterial diseases, inparticular for diseases caused by infection with bacteria selected fromthe group consisting of mycobacterium such as mycobacteriumtuberculosis, mycobacterium avium and mycobacterium leprae. Thecompounds of formula I of the present invention may further be useful inthe treatment of other infectious diseases, such as chlamydia, fungaldiseases, in particular fungal diseases selected from the groupconsisting of candidiasis, aspergillosis and cryptococcal meningitis,and parasitic diseases such as Pneumocystis carni, pneumonia,cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infectionand leishmaniasis.

Thus, the expression “diseases which are mediated by TLR agonists” meansdiseases which may be treated by activation of the immune system withTLR7 and /or TLR8 agonists such as cancer and infectious diseases. Inparticular, the expression “diseases which are mediated by TLR agonists”means cancers or autoimmune diseases or infectious diseases selectedfrom the group consisting of viral diseases, bacterial diseases, fungaldiseases and parasitic diseases.

In a particular aspect, the expression “which are mediated by TLRagonists” relates to cancer selected from the group consisting ofbladder cancer, head and neck cancer, prostate cancer, colorectalcancer, kidney cancer, breast cancer, lung cancer, ovarian cancer,cervical cancer, pancreatic cancer, bowel and colon cancer, stomachcancer, thyroid cancer, melanoma, skin and brain tumors and malignanciesaffecting the bone marrow such as leukemias and lymphoproliferativesystems, such as Hodgkin's and non-Hodgkin's lymphoma; including theprevention and treatment of metastatic cancer and tumor recurrences, andparaneoplastic syndromes.

The invention also relates to pharmaceutical compositions comprising acompound of formula I as defined above and a pharmaceutically acceptablecarrier and/or adjuvant. More specifically, the invention relates topharmaceutical compositions useful for the treatment of diseases whichare which are mediated by TLR agonists.

Further, the invention relates to compounds of formula I as definedabove for use as therapeutically active substances, particularly astherapeutically active substances for the treatment of diseases whichare which are mediated by TLR agonists. In particular, the inventionrelates to compounds of formula I for use in the treatment of cancers orautoimmune diseases or infectious diseases selected from the groupconsisting of viral diseases, bacterial diseases, fungal diseases andparasitic diseases.

In another aspect, the invention relates to a method for the treatment aof diseases which are mediated by TLR agonists, which method comprisesadministering a therapeutically active amount of a compound of formulaIto a human being or animal. In particular, the invention relates to amethod for the treatment of cancers and infectious diseases selectedfrom the group consisting of viral diseases, bacterial diseases, fungaldiseases and parasitic diseases.

The invention further relates to the use of compounds of formula I asdefined above for the treatment of diseases which are mediated by TLRagonists.

In addition, the invention relates to the use of compounds of formula Ias defined above for the preparation of medicaments for the treatment ofdiseases which are mediated by TLR agonists. In particular, theinvention relates to the use of compounds of formula I as defined abovefor the preparation of medicaments for the treatment of cancers orautoimmune diseases or infectious diseases selected from the groupconsisting of viral diseases, bacterial diseases, fungal diseases andparasitic diseases.

In a further aspect, compounds of formula I can be in combination withone or more additional treatment modalities in a regimen for thetreatment of cancer.

Combination therapy encompasses, in addition to the administration of acompound of the invention, the adjunctive use of one or more modalitiesthat are effective in the treatment of cancer. Such modalities include,but are not limited to, chemotherapeutic agents, immunotherapeutics,anti-angiogenic agents, cytokines, hormones, antibodies,polynucleotides, radiation and photodynamic therapeutic agents. In aspecific aspect, combination therapy can be used to prevent therecurrence of cancer, inhibit metastasis, or inhibit the growth and/orspread of cancer or metastasis. As used herein, “in combination with”means that the compound of formula I is administered as part of atreatment regimen that comprises one or more additional treatmentmodalities as mentioned above. The invention thus also relates to amethod for the treatment of cancer, which method comprises administeringa therapeutically active amount of a compound of formula I incombination with one or more other pharmaceutically active compounds toa human being or animal.

Compounds of formula I can be used alone or in combination with one ormore additional treatment modalities in treating autoimmune diseases.

Combination therapy encompasses, in addition to the administration of acompound of the invention, the adjunctive use of one or more modalitiesthat aid in the prevention or treatment of autoimmune diseases. Suchmodalities include, but are not limited to, chemotherapeutic agents,immunotherapeutics, anti-angiogenic agents, cytokines, hormones,antibodies, polynucleotides, radiation and photodynamic therapeuticagents. As used herein, “in combination with” means that the compound offormula I is administered as part of a treatment regimen that comprisesone or more additional treatment modalities as mentioned above. Theinvention thus also relates to a method for the treatment of autoimmunediseases, which method comprises administering a therapeutically activeamount of a compound of formula I in combination with one or more otherpharmaceutically active compounds to a human being or animal.

In a further aspect, compounds of formula I can be used alone or incombination with one or more additional treatment modalities in treatinginfectious diseases.

Combination therapy encompasses, in addition to the administration of acompound of the invention, the adjunctive use of one or more modalitiesthat aid in the prevention or treatment of infectious diseases. Suchmodalities include, but are not limited to, antiviral agents,antibiotics, and anti-fungal agents. As used herein, “in combinationwith” means that the compound of formula I is administered as part of atreatment regimen that comprises one or more additional treatmentmodalities as mentioned above. The invention thus also relates to amethod for the treatment of infectious diseases, which method comprisesadministering a therapeutically active amount of a compound of formula Iin combination with one or more other pharmaceutically active compoundsto a human being or animal.

Pharmacological Test

The following tests were carried out in order to determine the activityof the compounds of formula I:

For TLR8 and TLR7 activity testing, HEK-Blue human TLR8 or TLR7 cells,respectively, (Invivogen, San Diego, Calif., USA) transfected with aSEAP reporter (secreted embryonic alkaline phosphatase) construct wereused, in which the reporter expression is regulated by the NF-κBpromoter upon stimulation for 24 hr. The reporter activity wasdetermined using Quanti Blue kit (Invivogen, San Diego, Calif., USA) ata wavelength of 640 nm.

EC₅₀ values were determined using Activity Base analysis (ID BusinessSolution, Limited).

The compounds according to formula I have an activity (EC₅₀ value) inthe above assay for human TLR8 in the range of 0.01 nM to 11 μM, moreparticularly of 0.01 nM to 3 μM and in the above assay for human TLR7 inthe range of 0.01 nM to 1 μM, in particular of 0.01 nM to 0.3 μM andmore particularly of 0.01 nM to 0.1 μM.

For example, the following compounds showed the following EC50 values inthe assay described above:

human TLR8 EC₅₀ human TLR7 EC₅₀ Example [μM] [μM] resiquimod 9.6 0.76 10.58 0.06 2 0.08 0.05 3 35 0.223 4 n.d. 0.027 5 10.5 0.9 6 2.9 0.195 71.08 0.139 8 0.256 0.134 9 0.054 0.055 10  2.7 0.152 11  2.9 0.131-(2-(2- 49 >100 Aminoethoxy)ethyl)- 2-(ethoxymethyl)-1H- imidazo[4,5-c]quinolin-4-amine CAS Reg. No. 557787-49-2 (Example 69 in US20030187016)

Pharmaceutical Compositions

The compounds of formula I and their pharmaceutically acceptable saltscan be used as medicaments, e.g., in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. Thecompounds of formula I and their pharmaceutically acceptable salts maybe administered by systemic (e.g., parenteral) or local (e.g., topicalor intralesional injection) administration. in some instances, thepharmaceutical formulation is topically, parenterally, vaginally,intrauterine, intranasal, or by inhalation administered. As describedherein, certain tissues may be preferred targets for the TLR. agonist.Thus, administration of the TLR agonist to lymph nodes, spleen, bonemarrow, blood, as well as tissue exposed to virus, are preferred sitesof administration.

In one aspect, the pharmaceutical formulation comprising the compoundsof formula I or its pharmaceutically acceptable salts is administeredparenterally. Parenteral routes of administration include, but are notlimited to, transdermal, transmucosal, nasopharyngeal, pulmonary anddirect injection. Parenteral administration by injection may be by anyparenteral injection route, including, but not limited to, intravenous(IV), including bolus and infusion (e.g., fast or slow), intraperitoneal(IP), intramuscular (IM), subcutaneous (SC) and intradermal (ID) routes.Transdermal and transmucosal administration may be accomplished by, forexample, inclusion of a carrier (e.g,, dimethylsulfoxide, DMSO), byapplication of electrical impulses (e.g., iontophoresis) or acombination thereof A variety of devices are available for transdermaladministration which may be used. Formulations of the compounds offormula I suitable for parenteral administration are generallyformulated USP water or water for injection and may further comprise pHbuffers, salts bulking agents, preservatives, and other pharmaceuticallyacceptable excipients.

Transdermal administration is accomplished by application of a cream,rinse, gel, etc. capable of allowing the TLR agonist to penetrate theskin and enter the blood stream. Compositions suitable for transdermaladministration include, but are not limited to, pharmaceuticallyacceptable suspensions, oils, creams and ointments applied directly tothe skin or incorporated into a protective carrier such as a transdermaldevice (so-called “patch”, Examples of suitable creams, ointments etc.can be found, for instance, in the Physician's Desk Reference,Transdermal transmission may also be accomplished by iontophoresis, forexample using commercially available patches which deliver their productcontinuously through unbroken skin for periods of several days or more.Use of this method allows for controlled transmission of pharmaceuticalcompositions in relatively great concentrations, permits infusion ofcombination drugs and allows for contemporaneous use of an absorptionpromoter. Administration via the transdermal and transmucosal routes maybe continuous or pulsatile.

Pulmonary administration is accomplished by inhalation, and includesdelivery routes such intranasal, transbronchial and transalveolarroutes. Formulations of compounds of formula I suitable foradministration by inhalation including, but not limited to, liquidsuspensions for forming aerosols as well as powder forms for dry powderinhalation delivery systems are provided. Devices suitable foradministration by inhalation include, but are not limited to, atomizers,vaporizers, nebulizers, and dry powder inhalation delivery devices.Other methods of delivering to respiratory mucosa include delivery ofliquid formulations, such as by nose drops. Administration by inhalationis preferably accomplished in discrete doses (e.g., via a metered doseinhaler), although delivery similar to an infusion may be accomplishedthrough use of a nebulizer.

The compounds of formula I and pharmaceutically acceptable salts thereofmay also be administered orally, e.g., in the form of tablets, coatedtablets, dragées, hard and soft gelatine capsules.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable salts, optionally in combination with other therapeuticallyvaluable substances, into a galenical administration form together withsuitable, non-toxic, inert, therapeutically compatible solid or liquidcarrier materials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 1000 mg,especially about 1 to 300 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g., in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-100 mg, of a compound of formula I.

The following examples C1 to C3 illustrate typical compositions of thepresent invention, but serve merely as representative thereof.

Example C1

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula I 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesiumstearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example C2

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C3

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Polyethylene glycol 400 150.0 mg Aceticacid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by aceticacid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 11-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-aminea)1-(2-(Ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

4-Amino-2-(ethoxymethyl)-α,α-dimethyl-1H-Imidazo[4,5-c]quinoline-1-ethanol(CAN 144875-48-9, 1.6 g, 5.09 mmol) was combined with acetonitrile (60mL) to give a white suspension. Then triethylamine (1.77 mL, 12.7 mmol)and trityl chloride (1.7 g, 6.11 mmol) were added under Argon withstirring. The reaction mixture was irradiated in a microwave reactor at100° C. for 30 minutes. Upon stirring the mixture the productprecipitated and was isolated by filtration at 0° C., washed with coldacetonitrile and dried to yield the title compound (2.37 g, 83%) aswhite solid; MS (ESI): 557.5(MH⁺).

b) tert-Butyl2-(1-(2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylcarbamate

Sodium hydride dispersion in oil 60% (173 mg, 4.32 mmol) was combinedwith DMF (15 mL) to give a colorless suspension. The mixture was cooledto 0° C. with stirring, and at this temperature a solution of1-(2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol(1.85 g, 3.32 mmol) in DMF (15 mL) was added dropwise over a period of10 min. Afterwards the reaction mixture was stirred for 1 hour at 0° C.and for 30 minutes at room temperature to give a yellow solution. Tothis solution was added at 0° C.2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid-1,1-dimethylethylester (CAN 459817-82-4 , 964 mg, 4.32 mmol). The temperature was allowedto rise to room temperature and the mixture was stirred overnight. Themixture was poured into ice-water and extracted with ethyl acetate.Organic layers were washed with water/brine (2:1), combined, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography (silica gel, 0 to 100% ethyl acetate in heptane) togive the title compound (1.47 g, 63%) as white foam; LC-MS (UV peakarea, ESI) 98.7%, 700.3850 (MH⁺).

c)1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

tert-Butyl2-(1-(2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylcarbamate(1.45 g, 2.07 mmol) was combined with dichloromethane (DCM, 12 mL) togive a colorless solution. TFA (6.0 mL, 77.9 mmol) was added and themixture was stirred for 3 hours at room temperature. The reactionmixture was cooled to 0° C., 2N sodium hydroxide solution (40 mL) wasadded, and the basic solution was extracted with dichloromethane.Organic layers were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(silica gel, 0 to 10% methanol in DCM) to give the title compound (0.62g, 83%) as white solid; LC-MS (UV peak area, ESI) 97.5%, 358.2238 (MH⁺).

Example 21-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl2-aminoacetate a)2-(2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl)isoindoline-1,3-dione

4-Amino-2-(ethoxymethyl)-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol(CAN 144875-48-9, 3.0 g, 9.54 mmol) was combined with toluene (21.0 mL)to give a white suspension. 1,4-Diazabicyclo[2.2.2]octane (3.21 g, 28.6mmol) and phtaloyl chloride (1.65 mL, 11.5 mmol) were added withstirring and the reaction mixture was stirred at 110° C. for 4 hours.After cooling the mixture was diluted with ethyl acetate (300 mL) andwashed with 1 N hydrochloric acid. Phases were separated and the waterlayer was extracted with ethyl acetate. The organic layers werecombined, dried over MgSO₄, filtered and concentrated in vacuo. Uponstirring the residue with ethyl acetate (50 mL) the productprecipitated, was filtered and dried in vacuo (1.9 g). The mother liquorwas concentrated and yielded after flash chromatography (silica gel, 50g, 0% to 100% EtOAc in heptane) another batch of product (0.59 g). Intotal 2.49 g (59%) of the title compound was isolated as white solid;LC-MS (UV peak area, ESI) 96%, 445.2 (MH⁺).

b)1-(4-(1,3-Dioxoisoindolin-2-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl2-(1,3-dioxoisoindolin-2-yl)acetate

2-(2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl)isoindoline-1,3-dione(1600 mg, 3.6 mmol), 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid(CAN 4702-13-0, 2.22 g, 10.8 mmol) and 4-(1-pyrrolidinyl)-pyridine (800mg, 5.4 mmol) were combined with DCM (36 mL) to give a white suspension.N,N′-diisopropylcarbodiimide (1.68 mL, 10.8 mmol) and molecular sieveswere added. The reaction mixture was heated to 50° C. and stirred for 2hours and was, after cooling, filtered. The filtrate was diluted withDCM (150 mL) and washed with 1 N hydrochloric acid and water. Waterphases were extracted with DCM, organic phases were combined, dried overMgSO₄, filtered and concentrated in vacuo. Diisopropylurea was removedafter trituration with DCM/methanol by filtration, the filtrate wasconcentrated and the residue was purified by flash chromatography(silica gel, 0% to 100% ethyl acetate in heptane) to give a light yellowsolid. Crystallization from DMSO yielded a first crop of product (1.95g), and the mother liquor after concentration and preparative HPLCanother 0.13 g of product. In total 2.08 g (91%) of the title compoundwas isolated as white solid; LC-MS (UV peak area, ESI) 95.9%, 632.2157(MH⁺).

c)1-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl2-aminoacetate

1-(4-(1,3-Dioxoisoindolin-2-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl2-(1,3-dioxoisoindolin-2-yl)acetate (300 mg, 475 μmol) was combined withTHF (5 mL) to give a white suspension. To this suspension was addedhydrazine in water (1000 μl, 11.2 mmol) and the solution was stirred for0.75 hour at room temperature. The mixture was cooled to 0° C., 1Nhydrochloric acid (30 mL) and DCM (50 mL) were added. The whiteprecipitate a (phtalylhydrazide) was removed by filtration and theorganic phase was discarded. The aqueous phase was lyophilized and theresidue was taken up with acetonitrile (20 mL) and DIEA (pH 10). Afterevaporation of solvent, the residue was purified by preparative HPLC(Gemini NX 3u 50×4.6 mm; acetonitrile/water/Et₃N) to give the titlecompound (111 mg, 63%) as amorphous white solid; LC-MS (UV peak area,ESI) 99%, 372.4 (MH⁺).

Example 3N-(2-(1-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)nicotinamide

Nicotinic acid (11.4 mg, 92.3 μmol) was combined with DMF (1.0 mL) togive a colorless solution. To this solution was added TBTU (29.6 mg,92.3 μmol), and DIEA (54.2 mg, 71.8 μl) were added. Finally1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(30 mg, 83.9 μmol) was added and the reaction mixture was stirred for 1hour at room temperature. Volatiles were removed in high vacuum at 40°C. The residue was dissolve in a mixture of ethyl acetate (5 mL) andmethanol (0.5 mL). 1N sodium hydroxide solution (1.5 mL) was added andafter a few minutes stirring the layers were separated. The aqueouslayer was extracted with ethyl acetate. The organic phases were combineddried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (silica gel-NH2, 0% to 10% methanol inDCM) to give the title product (33 mg, 85%) as white foam; LC-MS (UVpeak area, ESI) 88%, 463.2459 (MH⁺).

Example 4N-(2-(1-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)acetamide

1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(32 mg, 89.5 μmol) was combined with DCM (1.0 mL) to give a colorlesssolution. To this solution was added triethylamine (25.0 μL, 179 μmol)and acetyl chloride (7.00 μL, 98.5 μmol) and the reaction mixture wasstirred 18 hours at room temperature. After concentrating the mixture invacuo the residue was purified by flash chromatography (silica gel-NH₂,0% to 10% methanol in DCM) to give the title compound (19 mg, 53%) aswhite foam; LC-MS (UV peak area, ESI) 97%, 400.2348 (MH⁺).

Example 53-(2-(1-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)propan-1-ola)2-(Ethoxymethyl)-1-[2-methyl-2-[2-(3-trityloxypropylamino)ethoxy]propyl]-imidazo[4,5-c]quinolin-4-amine

1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(50 mg, 140 μmol) and 3-(triphenylmethoxy)-propanal (CAN 67057-68-5;44.3 mg, 140 μmol) were combined with ethanol (500 μL) to give a lightyellow suspension. The mixture was stirred for 2 hours at roomtemperature. Afterwards sodium borohydride (5.82 mg, 154 μmol) was addedand stirring at room temperature continued overnight. The mixture wasstirred with water (2 mL) and ethyl acetate (5 mL), dried by passagethrough a ChemElut® cartridge and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel-NH2, 0% to100% ethyl acetate in heptane) followed by another flash chromatography(silica gel, 0 to 10% methanol in ethyl acetate) to give the titlecompound (10 mg, 11%) as yellowish gum; LC-MS (UV peak area, ESI) 89%,658.5 (MH⁺).

b)3-(2-(1-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)propan-1-ol

2-(Ethoxymethyl)-1-[2-methyl-2-[2-(3-trityloxypropylamino)ethoxy]propyl]-imidazo[4,5-c]quinolin-4-amine(10 mg, 15.2 μmol) was combined with DCM (1 mL) to give a colorlesssolution. TFA (100 μl, 1.3 mmol) was added and the reaction mixture wasstirred at room temperature for 5 hours. The mixture was concentrated invacuo and the residue was purified by flash chromatography (silicagel-NH2, 0% to 30% methanol in ethyl acetate) to give the title compound(2.3 mg, 36%) as colorless gum; LC-MS (UV peak area, ESI) 95.6%,416.2661 (MH⁺).

Example 6 tert-Butyl6-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)-6-oxohexylcarbamate

6-(tert-Butoxycarbonylamino)hexanoic acid (197 mg, 850 μmol) wascombined with DMF (10.9 mL) to give a colorless solution.O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 300 mg, 936 μmol) and N,N-diisopropylethylamine (DIEA, 728 μl,4.25 mmol) were added with stirring in an inert atmosphere. Then1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(Example 1c, 304 mg, 850 μmol) was added and the mixture was stirred for2 hours at room temperature. The mixture was concentrated in vacuo,dissolved in ethyl acetate (5 mL), stirred for 1 min with cold sodiumhydroxide solution (1 N) and dried by passing through ChemElut® (10 g).The organic phase was concentrated in vacuo again and the residue waspurified by flash chromatography (silica gel, 10% methanol indichloromethane) to give the title compound (0.135 g, 23%) as lightbrown oil; LC-MS (UV peak area, ESI) 83%, 571.5 (MH⁺).

Example 7 (E)-Ethyl3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)acrylatea)5-Amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile

Triethylamine (5.28 ml, 37.9 mmol) was added with stirring to asuspension of 2-aminomalononitrile 4-methylbenzenesulfonate (8 g, 31.6mmol) in THF (120 ml) to give a light brown solution.1,1,1,2-Tetraethoxyethane (7.82 g, 37.9 mmol) was added and the reactionmixture was stirred under argon at reflux temperature. After 4 h anadditional amount of 2.3 g 1,1,1,2-tetraethoxyethane was added and themixture heated for another 2 h. The mixture was allowed to cool to roomtemperature, triethylamine (5.28 ml, 37.9 mmol) and1-amino-2-methylpropan-2-ol (3.63 ml, 37.9 mmol) were added and thereaction was stirred overnight. The mixture was concentrated in vacuo,and the residue was partitioned between ethyl acetate (200 mL, 2×150 mL)and sodium bicarbonate solution (2 M, 100 mL). The organic phases werecombined, dried over MgSO₄, concentrated in vacuo and purified by flashchromatography (silica gel, 0% to 100% ethyl acetate in heptane) to givethe title compound after a crystallization step from heptane (4.47 g,59%) as white crystalline solid; LC-MS (UV peak area, ESI) 100%,239.1514 (MH+).

b)2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-iodo-1H-imidazole-4-carbonitrile

Diiodomethane (14.5 ml, 180 mmol) was added under argon with stirring toa suspension of5-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazole-4-carbonitrile(4.36 g, 18.3 mmol) in chloroform (170 mL). The reaction mixture washeated to 80° C., a solution of isoamyl nitrite (9.86 ml, 73.2 mmol) inchloroform (30 mL) was added with a syringe pump over a period of 40 minand the mixture was stirred for another 30 min at 80° C. After coolingto room temperature the mixture was concentrated in vacuo and purifiedby flash chromatography (silica gel, 20% to 50% ethyl acetate inheptane) to give the title compound (3.66 g, 57%) as brown oil; LC-MS(UV peak area, ESI) 90%, 350.0374 (MH⁺).

c) Methyl3-amino-4-[5-cyano-2-(ethoxymethyl)-3-(2-hydroxy-2-methylpropyl)-1H-imidazol-4-yl]benzoate

In an inert atmosphere2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-iodo-1H-imidazole-4-carbonitrile(3.66 g, 10.5 mmol) was combined with dimethoxyethane (43 mL) to give alight brown solution. To this solution were added Pd(OAc)₂ (118 mg, 524μmol), triphenylphosphine (275 mg, 1.05 mmol) and methyl3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.36 g,15.7 mmol) with stirring. Finally Na₂CO₃ (2 M, 15.7 mL, 31.4 mmol) wasadded. The reaction mixture was heated to 100° C. and stirred for 1hour. After cooling to room temperature the mixture was partitionedbetween ethyl acetate (70 mL, 2×50 mL) and water (70 mL). The organicphases were combined, dried over MgSO₄, concentrated in vacuo andpurified by flash chromatography (silica gel, 0% to 100% ethyl acetatein heptane) to give the title compound (2.79 g, 71%) as light brown foamthat was used in the next step without further purification.

d) Methyl4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-7-carboxylate

Methyl3-amino-4-(4-cyano-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazol-5-yl)benzoate(2.79 g, 7.49 mmol) was combined with a solution of HCl in dioxane (4M,56.2 mL, 225 mmol) to give an orange solution. The reaction mixture washeated to 90° C. under argon with stirring. After 1 h at 90° C. themixture was cooled to room temperature and concentrated in vacuo toobtain a beige solid. The solid was dissolved in ethyl acetate (500 mL)washed with a mixture of water (100 mL) and saturated sodium bicarbonatesolution (250 mL). The water phase was extracted with ethyl acetate(2×250 mL), organic phases were combined, dried with MgSO₄ andconcentrated in vacuo to obtain a yellow solid (3.05 g). The solidmaterial was re-crystallized from ethyl acetate /heptane to give thetitle compound (2.4 g, 86%) as light yellow solid; LC-MS (UV peak area,ESI) 99%, 373.1884 (MH+).

e) Methyl2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylate

The title compound was synthesized in analogy to Example la, usingmethyl4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-7-carboxylateas starting material and isolated (0.77 g, 96%) as light brown solid;LC-MS (UV peak area, ESI) 96%, 615.4 (MH⁺).

f)2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylicacid

Sodium hydroxide solution (1 N, 3.51 ml) was added to methyl2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylate(540 mg, 878 μmol) dissolved in THF (6.21 mL) and methanol (621 μL). Thereaction mixture was stirred for 120 hours at room temperature andconcentrated in vacuo. The residue was partitioned between ethyl acetate(30 mL) and cold 1M HCl solution (5 mL). The aqueous layer was extractedwith ethyl acetate (2×50 mL). Organic layers were washed with water (20mL) and brine (20 mL), combined, dried with MgSO₄, and concentrated invacuo to obtain the title compound (0.499 g, 94%) as white solid; LC-MS(UV peak area, ESI) 99%, 601.3 (MH⁺).

g)2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-N-methoxy-N-methyl-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxamide

To a solution of2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylicacid (484 mg, 741 μmol) in DMF (5.19 mL) in an inert atmosphere wasadded TBTU (357 mg, 1.11 mmol), DIEA (388 μL, 2.22 mmol) andN,O-dimethylhydroxylamine hydrochloride (108 mg, 1.11 mmol) withstirring. The reaction mixture was stirred for 1 h at room temperatureand afterwards the mixture was concentrated in vacuo. The residue waspartitioned between ethyl acetate (40 mL, 2×20 mL) and water (40 mL).The organic phases were washed with water (2×20 mL), combined, driedover MgSO₄, concentrated in vacuo and purified by flash chromatography(silica gel, 50% to 100% ethyl acetate in heptane) to give the titlecompound (0.53 g, quant.) as white foam; LC-MS (UV peak area, ESI) 92%,644.4 (MH⁺).

h)2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carbaldehyde

To a solution of2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-N-methoxy-N-methyl-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxamide(520 mg, 808 μmol) in THF (7 mL) in an inert atmosphere was added withstirring at 0° C. a solution of lithium aluminum hydride in THF (1 M,404 μl, 404 μmol). The mixture was stirred 1 h at 0° C., saturatedammonium chloride solution (10 mL) was added slowly and finally water(20 mL) and ethyl acetate (30 mL) were added. The phases were separated,the water layer was extracted with ethyl acetate (30 mL), and theorganic phases were washed with water (20 mL), combined, dried withMgSO₄, and concentrated in vacuo to give the title compound (0.49 g,quant.) as white foam (LC-MS (UV peak area, ESI) 83%, 585.4 (MH⁺)) thatwas used in the next step without further purification.

i) Ethyl(E)-3-[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate

(Carbethoxymethylene)triphenylphosphorane (422 mg, 1.21 mmol) was addedto a solution of2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carbaldehyde(472 mg, 808 μmol) in dichloromethane (8 mL) under argon. The reactionmixture was stirred for 20 h at room temperature and concentrated invacuo. Crystallization from dichloromethane and diethyl ether affordedthe title compound (0.399 g, 75%) as white solid, LC-MS (UV peak area,ESI) 89%, 655.4 (MH⁺).

j) Ethyl(E)-3-[1-[2-[2-(tert-butoxycarbonylamino)ethoxy]-2-methylpropyl]-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate

The title compound was synthesized in analogy to Example 1b, using ethyl(E)-3-[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoateas starting material and isolated (0.28 g, 42%) as white solid; LC-MS(UV peak area, ESI) 76%, 798.6 (MH⁺).

k) Ethyl(E)-3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)imidazo[4,5-c]quinolin-7-yl)prop-2-enoate

The title compound was synthesized in analogy to Example 1c, using ethyl(E)-3-[1-[2-[2-(tert-butoxycarbonylamino)ethoxy]-2-methylpropyl]-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoateas starting material and isolated (21 mg, 34%) as white solid; LC-MS (UVpeak area, ESI) 93%, 456.4 (MH⁺).

Example 8 Ethyl3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoatehydrochloride a) Ethyl3-[1-[2-[2-(tert-butoxycarbonylamino)ethoxy]-2-methylpropyl]-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate

Palladium on carbon 10% (100 mg, 940 μmol) in ethanol (10 mL) was addedto a suspension of (E)-ethyl3-(1-(2-(2-(tert-butoxycarbonylamino)ethoxy)-2-methylpropyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl)acrylate(280 mg, 351 μmol) in ethyl acetate (30 mL). The mixture was stirred for6 h in a hydrogen atmosphere at room temperature, filtered and solventwas removed in vacuo. The residue was purified by flash chromatography(silica gel-NH₂, 0% to 100% ethyl acetate in heptane) to give the titlecompound (0.163 g, 58%) as white solid; LC-MS (UV peak area, ESI) 74%,800.5 (MH³⁰ ).

b) Ethyl3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoatehydrochloride

The title compound was synthesized in analogy to Example 1c, using ethyl3-[1-[2-[2-(tert-butoxycarbonylamino)ethoxy]-2-methylpropyl]-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl]propanoateas starting material and isolated (15 mg, 56%) as white solid; LC-MS (UVpeak area, ESI) 93%, 458.4 (MH⁺).

Example 9 Ethyl3-(4-amino-1-(2-(2-aminoacetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoatea) Ethyl3-[4-[bis(benzyloxycarbonyl)amino]-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate

To a suspension of ethyl3-(4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoatehydrochloride (300 mg, 665 μmol), DMAP (15 mg, 123 μmol) and DIEA (1.86ml, 10.6 mmol) in dichloromethane (6 mL), benzyl chloroformate (380 μl,2.66 mmol) was added. The reaction mixture stirred at room temperaturefor 20 h, more benzyl chloroformate (908 60 μl, 5.32 mmol) was added andstirring continued for another 6 h. Afterwards the mixture was pouredinto dichloromethane (50 mL), extracted with HCl (1M, 20 mL) and water(20 mL). The aqueous layer was extracted with dichloromethane (50 mL),organic phases were combined, dried with MgSO₄ and concentrated invacuo. The residue was purified by flash chromatography (silica gel, 0%to 100% ethyl acetate in heptane) to give the title compound (0.459 g,quant.) as colorless oil; LC-MS (UV peak area, ESI) 86%, 683.5 (MH⁺).

b) Ethyl3-[4-(benzyloxycarbonylamino)-1-[2-[2-(dibenzylamino)acetyl]oxy-2-methylpropyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoate

To a suspension of ethyl3-(4-(bis(benzyloxycarbonyl)amino)-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate(300 mg, 439 μmol), 2-(dibenzylamino)acetic acid (337 mg, 1.32 mmol) andDMAP (107 mg, 879 μmol) in dichloromethane (4 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (253 mg, 1.32 mmol) andmolecular sieves (300 mg). After 1 h stirring at room temperaturestarting materials had dissolved, stirring at room temperature continuedfor 6 h and the mixture was left standing over the weekend. The residuewas diluted with dichloromethane (50 mL) and washed with HCl (1 M, 20mL) and water (20 mL). The aqueous phase was extracted withdichloromethane (50 mL), organic phases were combined, dried with MgSO₄and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 0% to 100% ethyl acetate in heptane) to givethe title compound (182 mg, 52%) as light yellow oil; LC-MS (UV peakarea, ESI) 98%, 784.6 (MH⁺).

c) Ethyl3-(4-amino-1-(2-(2-aminoacetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate

Ethyl3-(4-(benzyloxycarbonylamino)-1-(2-(2-(dibenzylamino)acetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate(182 mg, 232 μmol) was combined with ethyl acetate (20 mL) to give alight yellow solution. Palladium on carbon 10% (600 mg, 232 μmol) wasadded and the mixture was stirred for 20 h at room temperature under H₂.Afterwards the mixture was filtered through celite® and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 20g, 0% to 30% methanol in THF) to 27 mg of an impure sample thatwas further purified by preparative HPLC to give the title compound (6mg, 5%) as light yellow oil; LC-MS (UV peak area, ESI) 79%, 516.5(MHCOO⁻).

Example 101-(2-(2-Aminoethoxy)-2-methylpropyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-aminea) 2-Methyl-1-(2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-2-ol

To a solution of 1-(3-aminoquinolin-4-ylamino)-2-methylpropan-2-ol (CAN129655-59-0, 0.94 g, 4.06 mmol) in dichloromethane (9.5 mL) in an inertatmosphere was added dropwise with stirring at room temperature over aperiod of 6 min a solution of hexanoyl chloride (422 μl, 4.47 mmol) indichloromethane (6.4 mL). After 3 h additional hexanoyl chloride (192μl, 2.03 mmol) was added and stirring continued for another hour andfinally the mixture was concentrated in vacuo. The residue wasre-dissolved in ethanol (13.5 mL) and, after addition of sodiumhydroxidesolution (1 M, 10.8 mL) the mixture was heated with stirring in argon to90° C. After 75 min the mixture was allowed to cool to room temperatureand concentrated in vacuo. The residue was stirred with ethyl acetate(30 mL) and water (5 mL) dried by filtration over ChemElut® and ethylacetate was removed in vacuo. The residue was purified by flashchromatography (silica gel-NH₂, 0% to 100% ethyl acetate in heptane) togive the title compound (747 mg, 89%) as yellow oil; LC-MS (UV peakarea, ESI) 95%, 312.2 (MH⁺).

b)2-Methyl-1-(5-oxido-2-pentyl-1H-imidazo[4,5-c]quinolin-5-ium-1-yl)propan-2-ol

To a solution of2-methyl-1-(2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-2-ol (457 mg,1.36 mmol) in dichloromethane (21.2 mL) was added with stirring3-chloroperoxybenzoic acid (283 mg, 1.64 mmol) in one portion. Thereaction mixture was stirred for 16 h at room temperature. Afterwardsthe mixture was partitioned between cold dichloromethane (50 mL) andsodium hydroxide solution (1 M, 20 mL). The organic phase was washedwith cold water (20 mL) and brine (20 mL) and aqueous phases wereextracted with dichloromethane (2×50 mL). All organic phases werecombined, dried with MgSO₄, filtered and concentrated in vacuo, Theresidue was purified by flash chromatography (silica gel, 0% to 20%methanol in dichloromethane) to give the title compound (360 mg, 80%) aslight yellow solid; LC-MS (UV peak area, ESI) 99%, 328.2 (MH⁺).

c)1-(4-Amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol

To a solution of2-methyl-1-(5-oxido-2-pentyl-1H-imidazo[4,5-c]quinolin-5-ium-1-yl)propan-2-ol(353 mg, 1.08 mmol) in anhydrous dichloromethane (47.6 mL) was addedbenzoyl isocyanate (90%, 286 μl, 2.05 mmol) with stirring in argonatmosphere at room temperature. The reaction mixture was stirred atreflux temperature for 35 min. The mixture was then concentrated invacuo. The residue was then combined with anhydrous methanol (17.0 mL)to give a white suspension. Sodium methoxide solution in methanol (1.7ml, 9.16 mmol) was added and the mixture was stirred for 1 h at 70° C.Afterwards the mixture was cooled to room temperature and solvents wereremoved in vacuo. The residue was partitioned between ethyl acetate (30mL) and water (15 mL), dried by passage through a ChemElut® cartridgeand concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 0% to 10% methanol in dichloromethane) togive the title compound (221 mg, 61%) as white solid; LC-MS (UV peakarea, ESI) 98%, 327.2185 (MH⁺).

d)2-Methyl-1-[2-pentyl-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]propan-2-ol

The title compound was synthesized in analogy to Example 1a, using1-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-olas starting material and isolated (230 mg, 71%) as white crystallinesolid; LC-MS (UV peak area, ESI) 99%, 569.3 (MH⁺).

f) tert-ButylN-[2-[1,1-dimethyl-2-[2-pentyl-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy]ethyl]carbamate

The title compound was synthesized in analogy to Example 1b, using2-methyl-1-[2-pentyl-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]propan-2-olas starting material and isolated (306 mg, quant.) as light yellow oil;LC-MS (UV peak area, ESI) 53%, 712.2 (MH⁺).

g)1-(2-(2-Aminoethoxy)-2-methylpropyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine

The title compound was synthesized in analogy to Example 1c, usingtert-butylN-[2-[1,1-dimethyl-2-[2-pentyl-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy]ethyl]carbamateas starting material and isolated (30 mg, 36%) as white solid; LC-MS (UVpeak area, ESI) 98%, 370.2622 (MH⁺).

Example 111-(2-(2-Aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride a)1-[7-Bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

The title compound was synthesized in analogy to Example 1a, using1-(4-amino-7bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-olas starting material and isolated (100 mg, 88%) as light browncrystalline solid; LC-MS (UV peak area, ESI) 95%, 637.3 (MH+).

b) tert-ButylN-[2-[2-[7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethyl-ethoxy]ethyl]carbamate

The title compound was synthesized in analogy to Example 1b, using1-[7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-olas starting material and isolated (20 mg, 44%) as white solid which wasused without further purification in the next step.

c)1-(2-(2-Aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride

The title compound was synthesized in analogy to Example 1c, usingtert-butylN-[2-[2-[7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethyl-ethoxy]ethyl]carbamateas starting material and isolated (7 mg, 58%) as white solid; LC-MS (UVpeak area, ESI) 99%, 438.2 (MH+).

What is claimed is:
 1. A compound of formula I

wherein R¹ is C₁₋₇-alkyl or C₁₋₇-alkoxy-C₁₋₇-alkyl; R² is selected fromthe group consisting of hydrogen, halogen, hydroxyl, hydroxy-C₁₋₇-alkyl,alkoxy-C₁₋₇-alkyl, carboxyl, carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl,aminocarbonyl-C₁₋₇-alkyl, aminocarbonyl-C₂₋₇-alkenyl,C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl,C₁₋₇-alkylamino-carbonyl-C₂₋₇-alkenyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkyl-sulfonyl-C₁₋₇-alkyl,sulfamoyl-C_(1-7—)alkyl, C₁₋₇-alkyl-sulfamoyl-C₁₋₇-alkyl, phenyl, saidphenyl being unsubstituted or substituted with one, two or three groupsselected from the group consisting of C₁₋₇-alkyl, C₁₋₇-cycloalkyl,halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, hydroxy,hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy, cyano, carboxyl, C₁₋₇-alkoxycarbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl,hydroxy-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl,carboxyl-C₁₋₇-alkylsulfonyl, C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl,amino, C₁₋₇-alkylamino, di-C₁₋₇-alkylamino and nitro, and phenoxy, saidphenoxy group being unsubstituted or substituted with one, two or threegroups selected from the group consisting of C₁₋₇-alkyl,C₁₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy,hydroxy, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy, cyano, carboxyl,C₁₋₇-alkoxycarbonyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkyl-sulfonyl, hydroxy-C₁₋₇-alkylsulfonyl,C₁₋₇-alkoxy-C₁₋₇-alkylsulfonyl, carboxyl-C₁₋₇-alkylsulfonyl,C₁₋₇-alkoxy-carbonyl-C₁₋₇-alkylsulfonyl, amino, C₁₋₇-alkylamino,di-C₁₋₇-alkylamino and nitro; R³ is hydrogen or halogen; R⁴ is selectedfrom the group consisting of —O—(CH₂)_(m)—NHR⁵, and—O—(CO)—(CH₂)_(n)—NHR⁶, wherein m is selected from 1, 2 or 3, n isselected from 1 or 2, R⁵ is selected from the group consisting ofhydrogen, hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C₁₋₇-alkyl andC₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl, and R⁶ is selected fromthe group consisting of hydrogen, hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl,C₁₋₇-alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl,carboxyl-C₁₋₇-alkyl and C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl,or a pharmaceutically acceptable salt thereof.
 2. A compound of formulaI according to claim 1, wherein R¹ is C₁₋₇-alkoxy-C₁₋₇-alkyl.
 3. Acompound of formula I according to claim 1, wherein R¹ is ethoxyethyl.4. A compound of formula I according to claim 1, wherein R³ is hydrogen.5. A compound of formula I according to claim 1, wherein R⁴ is—O—(CH₂)_(m)—NHR⁵ and wherein m is selected from 1, 2 or 3 and whereinR⁵ is selected from the group consisting of hydrogen,hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl,phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C₁₋₇-alkyl andC₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl.
 6. A compound of formulaI according to claim 1, wherein m is
 2. 7. A compound of formula Iaccording to claim 1, wherein R⁵ is selected from the group consistingof hydrogen, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkylcarbonyl, heteroarylcarbonyland C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl.
 8. A compound offormula I according to claim 1, wherein R⁵ is hydrogen.
 9. A compound offormula I according to claim 1, wherein R⁴ is —O—(CO)—(CH₂)_(n)—NHR⁶ andwherein n is selected from 1 or 2 and wherein R⁶ is selected from thegroup consisting of hydrogen, hydroxy-C₁₋₇-alkyl, amino-C₁₋₇-alkyl,C₁₋₇-alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl,carboxyl-C₁₋₇-alkyl and C₁₋₇-alkoxycarbonyl-amino-C₁₋₇-alkyl-carbonyl.10. A compound of formula I according to claim 1, wherein n is
 1. 11. Acompound of formula I according to claim 1, wherein R⁶ is hydrogen. 12.A compound of formula I according to claim 1, wherein R² is selectedfrom the group consisting of hydrogen, halogen, hydroxyl,hydroxy-C₁₋₇-alkyl, alkoxy-C₁₋₇-alkyl, carboxyl, carboxyl-C₁₋₇-alkyl,carboxyl-C₂₋₇-alkenyl, aminocarbonyl-C₁₋₇-alkyl,aminocarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl,C₁₋₇-alkylamino-carbonyl-C₂₋₇-alkenyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkyl-sulfonyl-C₁₋₇-alkyl,sulfamoyl-C_(1-7—)alkyl and C₁₋₇-alkyl-sulfamoyl-C₁₋₇-alkyl.
 13. Acompound of formula I according to claim 1, wherein R² is selected fromthe group consisting of hydrogen, halogen,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl and C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl. 14.A compound of formula I according to claim 1, wherein R² is hydrogen.15. A compound of formula I according to claim 1, selected from thegroup consisting of1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl2-aminoacetate,N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)nicotinamide,N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)acetamide,3-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)propan-1-ol,tert-butyl6-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)-6-oxohexylcarbamate,ethyl(E)-3-[4-amino-1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate,ethyl3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,ethyl3-(4-amino-1-(2-(2-aminoacetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,1-(2-(2-aminoethoxy)-2-methylpropyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine,and1-(2-(2-aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,or a pharmaceutically acceptable salt thereof.
 16. A compound of formulaI according to claim 1, which is1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,or a pharmaceutically acceptable salt thereof.
 17. A compound of formulaI according to claim 1, selected from the group consisting of1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl2-aminoacetate, ethyl3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,or a pharmaceutically acceptable salt thereof.
 18. A compound of formulaI according to claim 1, or a pharmaceutically acceptable salt thereof,for use as medicament.
 19. A compound of formula I according to claiml,or a pharmaceutically acceptable salt thereof, for use as medicament forthe treatment of diseases which can be mediated with TLR agonists.
 20. Apharmaceutical composition comprising a compound of formula I accordingto claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier and/or adjuvant.
 21. The use of acompound of formula I according to claim 1, or a pharmaceuticallyacceptable salt thereof, for the preparation of a medicament for thetreatment of diseases which can be mediated with TLR agonists,particularly for the treatment of cancer or autoimmune diseases orinfectious diseases.
 22. A method of treating cancer, an autoimmunedisease or infectious disease, the method comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof formula I in accordance with claim 1, or a pharmaceuticallyacceptable salt thereof.
 23. The method of claim 22 wherein the canceris bladder cancer, head and neck cancer, prostate cancer, colorectalcancer, kidney cancer, breast cancer, lung cancer, ovarian cancer,cervical cancer, pancreatic cancer, bowel cancer, colon cancer, stomachcancer, thyroid cancer, melanoma, brain cancer, leukemia, and Hodgkin'sor non-Hodgkin's lymphoma.
 24. The method of claim 22 wherein theautoimmune diseases is rheumatoid arthritis, Sjogren's syndrome,scleroderma, SLE, lupus nephritis, polymyositis/dermatomyositis,cryoglobulinemia, anti-phospholipid antibody syndrome, psoriaticarthritis, inflammatory bowel diseases, ulcerative colitis, Crohn'sdisease, autoimmune gastritis, pernicious anemia, autoimmune hepatitis,primary biliary cirrhosis, primary sclerosing cholangitis, celiacdisease, ANCA-negative vasculitis, ANCA-associated vasculitis,Churg-Strauss vasculitis, Wegener's granulomatosis, microscopicpolyangiitis, multiple sclerosis, opsoclonus myoclonus syndrome,myasthenia gravis, neuromyelitis optica, Parkinson's disease,Alzheimer's disease, glomerulonephritis, Goodpasture's syndrome,Berger's disease, psoriasis, urticaria, hives, pemphigus vulgaris,bullous pemphigoid, and cutaneous lupus erythematosus, thrombocytopenicpurpura, thrombotic thrombocytopenic purpura, post-transfusion purpura,autoimmune hemolytic anemia, atherosclerosis, uveitis, Behcet's disease,Raynaud's syndrome, insulin-dependent diabetes mellitus (IDDM),Addison's disease, Graves' disease, thyroiditis, food allergies, drugallergies, insect allergies, mastocytosis, eczema, or asthma.
 25. Themethod of claim 22 wherein the infectious disease is human papillomavirus, genital warts, common warts, plantar warts, herpes simplex virus,molluscum contagiosum, hepatitis B virus (HBV), hepatitis C virus (HCV),Dengue virus, variola virus, human immunodeficiency virus (HIV),cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus,enterovirus, adenovirus, coronavirus, influenza, mumps or parainfluenza.26. The method of claim 22 wherein the infectious disease is abacterial, fungal or parasitic disease selected from mycobacteriumtuberculosis, mycobacterium avium, mycobacterium leprae, chlamydia,candidiasis, aspergillosis, cryptococcal meningitis, Pneumocystiscarnii, pneumonia, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection or leishmaniasis.
 27. A process for themanufacture of a compound of formula I in accordance with claim 1, or apharmaceutically acceptable salt thereof, which process comprises a)reacting a compound of the formula II

wherein R¹, R² and R³ are as defined in claim 1 and PG is a protectinggroup, with a compound of the formula III

wherein m is as defined in claim 1, under basic conditions and removingthe protecting groups PG and Boc under acidic conditions to obtain acompound of the formula I-a

wherein R¹ to R³ and m are as defined in claim 1, and optionally furthercoupling the compound of formula I-a with an alcohol or acid of theformula R⁵—OH or and aldehyde of the formula R⁵═O to obtain a compoundof formula I-c

wherein R¹ to R³, m and R⁵ are as defined in claim 1, and, if desired,converting the compound obtained into a pharmaceutically acceptablesalt, or b) reacting an compound of the formula II-a

wherein R¹, R² and R³ are as defined in claim 1 and PG′ is a protectinggroup, with a carboxylic acid of the formula IV

wherein n is as defined in claim 1 and PG″ is a protecting group, in thepresence of a esterification agent and removing the protecting groupsPG′ and PG″ with a mild reducing agent to obtain a compound of theformula I-b

wherein R¹ to R³ and n are as defined in claim 1, and optionally furthercoupling the compound of formula I-a with an alcohol or acid of theformula R⁶—OH or and aldehyde of the formula R⁶═O to obtain a compoundof formula I-d

wherein R¹ to R³, m and R⁶ are as defined in claim 1, and, if desired,converting the compound obtained into a pharmaceutically acceptablesalt.